Young Donors Research Articles

It is a match! How donors and nonprofit organizations come together on a matching donation platform

AbstractOnline donation platforms have grown increasingly established in the past two decades. Among substantial research into donation‐based crowdfunding platforms in general, no studies address the intention to use matching donation platforms. The latter refers to a hypothetical product, not currently available on the market. It represents an extension of conventional donation platforms, aligning donors' preferences with NPOs and projects present on the platform. Drawing on the technology acceptance model (TAM), this exploratory study empirically investigates factors that influence the intention to use a matching donation platform. It also extends the TAM to include trust and donation processing factors and considers the perspectives of both donors and nonprofit organizations (NPOs) engaged in fundraising. The data include an online survey of 458 donors and 112 NPOs in Germany. The findings indicate that all factors, including trust and donation processing, within the extended TAM exert a significant impact on the intention to use a matching donation platform, and attitude toward the platform represents the most influential factor. This article also provides entrepreneurial recommendations for how a matching donation platform can be implemented and used in practice. For example, a matching donation platform should aim at younger donor target groups and provide NPOs with suitable options for processing donations.

"Okay, I respect this publicity stunt." A snapshot of public perceptions of an online game-based blood donation campaign.

With a decrease in young and first-time donors, applying gaming elements to blood donation may provide a novel means of encouraging young donors. In August 2023, the online game DiabloIV launched the Blood Harvest in which players were encouraged to donate blood products in the United States to receive virtual in-game rewards. Given the novelty of this independent initiative, our aim was to capture Diablov IV players opinions of the Blood Harvest through thematically analyzing their online discourse related to this blood donation campaign. We captured publicly available Twitter/X posts (n = 78) and engagement (n = 390) relevant to the Blood Harvest posted during and immediately after the campaign (October 13, 2023-November 27, 2023). Using thematic analysis, we identified 5 themes relating to the Blood Harvest campaign: (1) Positive perceptions and community motivations to donate, (2) Negative perceptions of the initiative and online game, (3) Players' inability to donate and participate in the initiative, (4) Incentives and incentive comparisons, and (5) Benefiting from positive associations focusing on the reputational gain that may be accessed through promoting blood donation. Situating a donation campaign in an established video game provides a novel opportunity to engage young donors. Through capturing public data, we provide a unique snapshot of how an online gaming community perceives and reacts to an independently initiated game-integrated blood donation campaign. This highlights key strengths of the approach as well as identifying potential risks for blood collection agencies.

Effect of Donor Age on Endocrine Function of and Immune Response to Ovarian Grafts.

Premature loss of ovarian function (POI) is associated with numerous negative side effects, including vasomotor symptoms, sleep and mood disturbances, disrupted urinary function, and increased risks for osteoporosis and heart disease. Hormone replacement therapy (HRT), the standard of care for POI, delivers only a subset of ovarian hormones and fails to mimic the monthly cyclicity and daily pulsatility characteristic of healthy ovarian tissue in reproductive-aged individuals whose ovarian tissue contains thousands of ovarian follicles. Ovarian tissue allografts have the potential to serve as an alternative, cell-based HRT, capable of producing the full panel of ovarian hormones at physiologically relevant doses and intervals. However, the risks associated with systemic immune suppression (IS) required to prevent allograft rejection outweigh the potential benefits of comprehensive and dynamic hormone therapy. This work investigates whether the age of ovarian tissue donor animals affects the function of, and immune response to, subcutaneous ovarian grafts. We performed syngeneic and semi-allogeneic ovarian transplants using tissue from mice aged 6-8 (D7) or 20-22 (D21) days and evaluated ovarian endocrine function and immune response in a mouse model of POI. Our results revealed that tissue derived from D7 donors, containing an ample and homogeneous primordial follicle reserve, was more effective in fully restoring hypothalamic-pituitary-ovarian feedback. In contrast, tissue derived from D21 donors elicited anti-donor antibodies with higher avidity compared to tissue from younger donors, suggesting that greater immunogenicity may be a trade-off of using mature donors. This work contributes to our understanding of the criteria donor tissue must meet to effectively function as a cell-based HRT and explores the importance of donor age as a factor in ovarian allograft rejection.

Pain is what hurts: An exploration of perception and management of pain in peripheral blood stem cell donors

BackgroundPain is a side effect of Granulocyte-Colony Stimulating Factor (G-CSF) administration. This prospective study investigates various aspects including pain perception occurring in Peripheral Blood Stem Cell (PBSC) donors. Materials and methodsRelated and unrelated PBSC donors were prospectively studied. Donors recorded pain symptoms during the four-day period of G-CSF administration using the McGill Pain Questionnaire, a Visual Analog Scale and a pain diary. ResultsThere were 208 donors included, 102 (49%) related and 106 (51%) unrelated donors. Ninety-two percent of all reported the occurrence of pain. Moderate or severe pain was reported by 52%. No differences were found between related and unrelated donors. Pain occurred more often in females (p = 0.035). Relatively young donors (age 16–30 years) more frequently showed to have pain in comparison to older donors (>50 years) (p = 0.006). Musculoskeletal pain was most frequently distributed in the gluteal and lower back region (65–71%). Irrespective of the pain location, pain was most often described as nagging, annoying, however tolerable. Donors experiencing pain most on days of G-CSF administration, most frequently occurring during relaxation or at night. Sleep-mode was often affected. The use of paracetamol (acetaminophen) was sufficient for all but one donor. ConclusionThis is the first study to describe different aspects of pain associated with G-CSF administration in donors. Although the observed pain was tolerable, it should never be neglected. Knowledge derived from this study is of use for staff members involved in donor information and care management.

Does NLRP1 Inflammasome Activation in Immune Cells in Kidney Transplantation Relate with Donor Organ Age?

Inflammation causes a wide range of health disorders. In this process, the formation of inflammasome complexes plays a key role. Although inflammasomes have been extensively studied during kidney disease, their role in kidney transplantation has not been fully elucidated. In this study, we evaluate the gene and protein expression of several components of the inflammasome pathway before and at several time points after kidney transplantation in a cohort of patients of different ages and receiving an organ from older or younger donors. Our findings indicate the activation of the NLRP1 inflammasome in several immune cell population, monocytes and CD4+ and CD8+ cells mainly, in renal transplant, and its level increases gradually in patients who receive an older organ, whereas it has the opposite effect on older patients who receive a younger organ. Despite treatment with immunosuppressants, inflammation persists in some patients. These results lead to the hypothesis that the donor's age is a critical factor in post-transplant inflammasome activation and that specific NLRP1 inflammasome inhibitors should be considered to increase the success of kidney transplantation long-term.

FOXO1 regulates wound-healing responses in human gingival fibroblasts.

Forkhead box-O 1 (FOXO1) is a transcription factor actively involved in oral wound healing at the epithelial barrier. However, less is known regarding the role of FOXO1 during the tissue repair response in the connective tissue compartment. This study explored the involvement of FOXO1 in the modulation of fibroblast activity related to wound healing. Primary cultures of human gingival fibroblasts were obtained from four healthy young donors. Myofibroblastic differentiation, collagen gel contraction, cell migration, cell spreading, and integrin activation were evaluated in the presence or absence of a FOXO1 inhibitor (AS1842856). Variations in mRNA and proteins of interest were evaluated through qRT-PCR and western blot, respectively. Distribution of actin, α-smooth muscle actin, and β1 integrin was evaluated using immunofluorescence. FOXO1 and TGF-β1 expression in gingival wound healing was assessed by immunohistochemistry in gingival wounds performed in C57BL/6 mice. Images were analyzed using ImageJ/Fiji. ANOVA or Kruskal-Wallis test followed by Tukey's or Dunn's post-hoc test was performed. All data are expressed as mean ± SD. p < .05 was considered statistically significant. FOXO1 inhibition caused a decrease in the expression of the myofibroblastic marker α-SMA along with a reduction in fibronectin, type I collagen, TGF-β1, and β1 integrin mRNA level. The FOXO1 inhibitor also caused decreases in cell migration, cell spreading, collagen gel contraction, and β1 integrin activation. FOXO1 and TGF-β1 were prominently expressed in gingival wounds in fibroblastic cells located at the wound bed. The present study indicates that FOXO1 plays an important role in the modulation of several wound-healing functions in gingival fibroblast. Moreover, our findings reveal an important regulatory role for FOXO1 on the differentiation of gingival myofibroblasts, the regulation of cell migration, and collagen contraction, all these functions being critical during tissue repair and fibrosis.

Heart transplantation with super-aged donors older than 65 years

PurposeThis study elucidated the clinical outcomes and serial allograft function of heart transplant (HTx) recipients who received hearts from super-aged donors ≥65 years of age. MethodsAdult HTx recipients between 1999 and 2022 were retrospectively reviewed and divided into two: donor age ≥65 years [super-aged donor, SAD group (n=12)] and donor age <65 years [younger donor, YD group (n=140)]. The primary endpoint was 3-year all-cause deaths after HTx. Secondary endpoints included all-cause death, hospitalization due to heart failure, acute cellular rejection, coronary intervention, and electronic device implantation. Serial cardiac function was assessed using echocardiography and right heart catheterization. ResultsCompared with the recipients in the YD group, those in the SAD group were older [age, 60 (interquartile range (IQR): 46–63) vs. 42 (IQR: 31–52) years, p<0.001], had a higher E/e’ and lower cardiac index (CI) 1 month after HTx [E/e’, 12.5 (IQR; 9.0–16.8) vs 9.5 (IQR: 7.5–11.9), p=0.026; CI, 2.8 (IQR: 2.4–3.2) L/min/m² vs. 3.3 (IQR: 2.9–3.9) L/min/m², p=0.014], and a comparable CI with higher E/e’ 1 year after HTx [E/e’, 12.0 (IQR: 8.6–13.3) vs. 7.9 (IQR: 6.6–10.6), p=0.007; CI, 3.6 (IQR: 3.2–4.3) L/min/m² vs. 3.6 (IQR: 3.3–4.2) L/min/m², p=0.99]. The 3-year overall survival was lower in the SAD group than in the YD group (81.5% vs. 97.8%, p=0.006), whereas the secondary endpoints were comparable. ConclusionSuper-aged donor hearts at ≥65 years can be used for HTx with acceptable outcomes and feasible allograft function in relatively older recipients.

In platelet single donor apheresis, platelet factor 4 levels correlated with donor's age and decreased during storage.

The human population is ageing worldwide. The World Health Organization estimated that the world's population of people aged60years and older will increase to at least 30%, coinciding with a growing frequency of cognitive and cardiovascular disease. Recently, in preclinical studies platelet Factor 4 (PF4) was presented as a pro-cognitive factor. This molecule is released by platelets in the circulation and could be present in blood products destined for transfusion. We wondered if PF4 levels are correlated to the age of the blood donor or to the storage time of platelet concentrates (PCs) intended for transfusion? We observed higher levels of PF4 in PCs from elderly donors compared to younger donors, while PC storage time did not determine PF4 levels expression.

Combined effect of unrelated donor age and HLA peptide-binding motif match status on HCT outcomes

AbstractAn HLA-mismatched unrelated donor who is class I peptide-binding motif (PBM)-matched is preferred over a PBM-mismatched donor. We hypothesized that using a younger donor (aged ≤35 years vs >35 years) could compensate for the inferior overall survival (OS) associated with PBM mismatches. We compared 6 groups: HLA-matched/younger donor (n = 10 531), HLA-matched/older donor (n = 3572), PBM-matched/younger donor (n = 357), PBM-matched/older donor (n = 257), PBM-mismatched/younger donor (n = 616), and PBM-mismatched/older donor (n = 339) in patients undergoing transplantation with conventional graft-versus-host disease prophylaxis. In multivariate analysis, HLA-matched/younger donors were associated with superior OS relative to any other group. Pairwise comparisons showed that donor age significantly impacted OS in both HLA-matched and HLA-mismatched groups. Moreover, younger donors appeared to negate the detrimental effect of PBM mismatching: the PBM-matched/younger donor group had similar OS as the HLA-matched/older donor group and the PBM-mismatched/younger donor group had similar OS as the PBM-matched/older donor group. Our study suggests that older unrelated donor age and PBM mismatching confer similarly adverse effects on OS and the impacts are additive, a finding which may widen the “acceptable” donor pool. The best OS is observed with HLA-matched/younger donors and the worst with PBM-mismatched/older donors. These findings should be validated with other data sets and with posttransplantation cyclophosphamide-based prophylaxis.

Cirbp suppression compromises DHODH-mediated ferroptosis defense and attenuates hypothermic cardioprotection in an aged donor transplantation model.

Hypothermia is commonly used to protect donor hearts during transplantation. However, patients transplanted with aged donor hearts still have severe myocardial injury and decreased survival rates, but the underlying mechanism remains unknown. Because aged hearts are not considered suitable for donation, the number of patients awaiting heart transplants is increasing. In this study, we examined whether hypothermic cardioprotection was attenuated in aged donor hearts during transplantation and evaluated potential therapeutic targets. Using a rat heart transplantation model, we found that hypothermic cardioprotection was impaired in aged donor hearts but preserved in young donor hearts. RNA-Seq showed that cold-inducible RNA-binding protein (Cirbp) expression was decreased in aged donor hearts, and these hearts showed severe ferroptosis after transplantation. The young donor hearts from Cirbp-KO rats exhibited attenuated hypothermic cardioprotection, but Cirbp overexpression in aged donor hearts ameliorated hypothermic cardioprotection. Cardiac proteomes revealed that dihydroorotate dehydrogenase (DHODH) expression was significantly decreased in Cirbp-KO donor hearts during transplantation. Consequently, DHODH-mediated ubiquinone reduction was compromised, thereby exacerbating cardiac lipid peroxidation and triggering ferroptosis after transplantation. A cardioplegic solution supplemented with CIRBP agonists improved hypothermic cardioprotection in aged donor hearts, indicating that this method has the potential to broaden the indications for using aged donor hearts in transplantation.

The Rejuvenation and Functional Restoration of Aged Adipose Stem Cells by DUXAP10 Knockdown via the Regulation of the miR-214-3p/RASSF5 Axis.

Adipose stem cell (ASC)-based therapies provide an encouraging option for tissue repair and regeneration. However, the function of these cells declines with aging, which limits their clinical transformation. Recent studies have outlined the involvement of long non-coding RNAs in stem cell aging. Here, we reanalyzed our published RNA sequencing (RNA-seq) data profiling differences between ASCs from young and old donors and identified a lncRNA named double homeobox A pseudogene 10 (DUXAP10) as significantly accumulated in aged ASCs. Knocking down DUXAP10 promoted stem cell proliferation and migration and halted cell senescence and the secretion of proinflammatory cytokines. In addition, DUXAP10 was located in the cytoplasm and functioned as a decoy for miR-214-3p. miR-214-3p was downregulated in aged ASCs, and its overexpression rejuvenated aged ASCs and reversed the harm caused by DUXAP10. Furthermore, Ras Association Domain Family Member 5 (RASSF5) was the target of miR-214-3p and was upregulated in aged ASCs. Overexpressing DUXAP10 and inhibiting miR-214-3p both enhanced RASSF5 content in ASCs, while DUXAP10 knockdown promoted the therapeutic ability of aged ASCs for skin wound healing. Overall, this study offers new insights into the mechanism of age-related ASC dysfunction and names DUXAP10 and miR-214-3p as potential targets for energizing aged stem cells.

Haploidentical stem cell donor choice for patients with acute myeloid leukemia: a study from the ALWP of the EBMT

AbstractThere is a paucity of information to guide the selection of the most suitable donor in haploidentical (Haplo) hematopoietic stem cell transplantation (HSCT). For this reason, from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we conducted a retrospective analysis to evaluate the impact of Haplo donor characteristics on outcomes in patients with acute myeloid leukemia (AML) who received graft-versus-host disease prophylaxis with posttransplant cyclophosphamide (PTCy). The primary end point was graft-versus-host disease (GVHD)-free and relapse-free survival (GRFS). Overall, 2200 patients were included. The median age of donors was 37 years (range, 8-71); 820 (37%) were females, including 458 (21%) who were used for male recipients. In addition, 1631 donors (74%) donated peripheral blood (PB). Multivariable analysis identified certain donor-related risk factors with a detrimental impact on transplant outcomes. The use of PB, older donors’ ages (>37 years), and female donors to male recipients negatively affected GRFS. Donor’s age and female donor-to-male recipient combination also affected nonrelapse mortality, leukemia-free survival, and overall survival. In conclusion, donor-related variables significantly influence outcomes in patients with AML after Haplo-HSCT with PTCy. When possible, younger donors and male donors for male recipients should be prioritized. The use of bone marrow can additionally prevent GVHD.

Exploring strategies to optimise outcomes in hepatitis-associated aplastic anaemia patients following haematopoietic stem cell transplantation

This study aimed to assess haematopoietic stem cell transplantation (HSCT) safety and efficacy while exploring strategies for optimising outcomes in patients with hepatitis-associated aplastic anaemia (HAAA). We retrospectively reviewed 35 HAAA patients who underwent HSCT at a large Chinese blood disease hospital between 2008 and 2022. HAAA patients receiving HSCT typically presented with severe (28.6%) and very severe (65.7%) AA. Male patients predominated (68.6%), with a median onset age of 23 years (range, 9–44). Haploidentical donor-HSCT and matched sibling donor-HSCT were in comparable proportions. The 5-year overall survival (OS) rate was 74.0%, with cumulative incidences of grade II–IV acute and chronic graft-versus-host disease (GVHD) at 37.1% and 22.4%, respectively. A diagnosis-to-HSCT interval ≥ 75 days, acute GVHD, and post-HSCT liver events (e.g., hepatic GVHD and a three-fold increase in aminotransferase or bilirubin) significantly worsened 5-year OS. In the multivariate models, recipients with sex-matched grafts had better OS, and those with younger male donors had a lower incidence of II–IV aGVHD. Higher HLA matching degree (HLA > = 7/10) was an independent prognostic factor associated with better OS and GFFS. A diagnosis-to-HSCT interval ≥ 75 days was predictive of post-transplant liver events in HAAA patients. In conclusion, HSCT was a safe and effective treatment for HAAA. Early transplantation, careful donor selection and improving post-transplant liver events were crucial to optimise outcomes.

Active Donor Management Goals in Serial Donors After Brain Death.

Management of potential organ donors is crucial in the donation process, considering that hemodynamic instability is quite common. In the this single-center retrospective observational study, we analyzed 87 utilized brain death donors consecutively admitted to our intensive care unit from January 1, 2019, to December 31, 2022. We assessed the achievement of donor management goals during the observation period, and we also evaluated whether the achieve-ment of donor goals differed between younger and older donors (arbitrary age cutoff of 65 years). In our series, mean age of donors was 67 ± 18 y, and organ-per-donor ratio was 2.3. The number of donor goals significantly increased during the 6-hour observation period (P < .001) and all donor goals were achieved in most donors (84/87) at the end of the observation period with no changes in the use and dose of vasoactive drugs. With respect to age, the number of donor goals was significantly higher in older donors at first evaluation, but goals significantly increased in both age subgroups of donors at the end of the 6-hour observation period. Our data strongly suggested that a strict hemodynamic monitoring schedule allows the achievement of donor goals both in older and in younger brain death donors. We confirmed our previous findings that hemodynamic management in brain death donors is influenced by age. A strict hemodynamic monitoring schedule of brain death donors is useful to consistently achieve donor goals.

Outcomes after lung transplantation from selected donors older than 70 years in a single centre: time to close the debate?

The aim of this study was to compare the outcomes of lung transplantations using grafts from donors aged over 70 years against those performed using younger donors. This retrospective single-centre analysis includes lung transplants conducted at our institution from January 2014 to June 2022. Lung recipients were classified into 2 groups based on donor age (group A <70 years; group B ≥70 years). Variables regarding demographics, peri and postoperative outcomes and survival were included. The statistical analysis approach included univariable analysis, propensity score matching to address imbalances in donor variables (smoking status), recipient characteristics (sex, age, diagnosis and lung allocation score) and calendar period and survival analysis. A total of 353 lung transplants were performed in this period, 47 (13.3%) using grafts from donors aged over 70 years. Donors in group B were more frequently women (70.2% vs 51.6%, P = 0.017), with less smoking history (22% vs 43%, P = 0.002) and longer mechanical ventilation time (3 vs 2 days, P = 0.025). Recipients in group B had a higher lung allocation score (37.5 vs 35, P = 0.035). Postoperative variables were comparable between both groups, except for pulmonary function tests. Group B demonstrated lower forced expiratory volume 1 s levels (2070 vs 2580 ml, P = 0.001). The propensity score matching showed a lower chance of chronic lung allograft dysfunction by 12% for group B. One-, three- and five-year survival was equal between the groups. The use of selected expanded-criteria donors aged over 70 years did not result in increased postoperative morbidity, early mortality or survival in this study.

Changes in the Transcription of Proliferation- and Apoptosis-Related Genes in Embryos in Women of Different Ages under the Influence of Extracellular Vesicles from Donor Follicular Fluid In Vitro.

We studied the influence of extracellular vesicles from the follicular fluid of a young donor on gene expression (MKI67, MYBL2, CCNB1, CCND1, CCNE1, CALM2, BAX, NDRG1, TP53I3, VEGF, VCAN, HAS2, CTSL2, PIBF1, RPL37, PFKP, GPX3, and AQP3) in embryos of women of different ages. According to nanoparticle tracking analysis data, the concentration of extracellular vesicles was 3.75±0.47×1011 particles/ml and the mean particle size was 138.78±9.90 nm. During co-culturing of the follicular fluid extracellular vesicles with blastocysts of young women, we observed significantly increased expression of mRNA for genes CTSL2, CCND1, CCNE1, VEGF and reduced expression of BAX gene mRNA in comparison with embryos in women of late reproductive age. We hypothesized that addition of extracellular vesicles of the oocyte follicular fluid from a young donor to the culture medium of embryos could slow down apoptosis process typical of blastocyst cells in women above 36 years.

Deciphering aging-associated molecular mechanisms in bone marrow derived hematopoietic stem cells in the elderly using NGS data

Aging is a complex process that is not yet fully understood. Despite advancements in research, a deeper understanding of the underlying biological mechanisms is necessary to develop interventions that promote healthy longevity. The aim of this study was to elucidate the complex mechanisms associated with healthy aging and longevity in healthy elderly individuals. The RNA sequencing (RNA-seq) data used in this study was obtained from the Gene Expression Omnibus (GEO) database (accession number GSE104406), which was collected from Fluorescent Activated Cell Sorting (FACS) of human bone marrow derived human hematopoietic stem cells (BM-HSCs) (Lineage-, CD34+, CD38-) young (18-30 years old) and aged (65-75 years old) donors who had no known hematological malignancy, with 10 biological replicates per group. The GEO RNA-seq Experiments Interactive Navigator (GREIN) software was used to obtain raw gene-level counts and filtered metadata for this dataset. Next generation knowledge discovery (NGKD) tools provided by BioJupies were used to obtain differentially regulated pathways, gene ontologies (GO), and gene signatures in the HSCs. Finally, theL1000 Characteristic Direction Signature Search Engine (L1000CDS2) tool was used to identify specific drugs that reverse aging-associated gene signatures in old but healthy individuals. The down-regulation of signaling pathways such as longevity regulation, proteasome, notch, apoptosis, nuclear factor kappa B (NFkB), and peroxisome proliferator-activated receptors (PPAR) signaling pathways in the HSCs of healthy elderly. GO functions related to negative regulation of bone morphogenetic protein (BMP), telomeric DNA binding, nucleoside binding, calcium -dependent protein binding, chromatin-DNA binding, SMAD binding, and demethylase activity were significantly downregulated in the BM-HSCs of the elderly compared to the healthy young group. Importantly, we identified potential drugs such as salermide, celestrol, cercosporin, dorsomorphin dihydrochloride, and LDN-193189 monohydrochloride that can reverse the aging-associated signatures in HSCs from healthy elderly. The analysis of RNA-seq data based on NGKD techniques revealed a plethora of differentially regulated pathways, gene ontologies, and drugs with anti-aging potential to promote healthspan in the elderly.

Deciphering aging-associated molecular mechanisms in bone marrow derived hematopoietic stem cells in the elderly using NGS data.

Aging is a complex process that is not yet fully understood. Despite advancements in research, a deeper understanding of the underlying biological mechanisms is necessary to develop interventions that promote healthy longevity. The aim of this study was to elucidate the complex mechanisms associated with healthy aging and longevity in healthy elderly individuals. The RNA sequencing (RNA-seq) data used in this study was obtained from the Gene Expression Omnibus (GEO) database (accession number GSE104406), which was collected from Fluorescent Activated Cell Sorting (FACS) of human bone marrow derived human hematopoietic stem cells (BM-HSCs) (Lineage-, CD34+, CD38-) young (18-30 years old) and aged (65-75 years old) donors who had no known hematological malignancy, with 10 biological replicates per group. The GEO RNA-seq Experiments Interactive Navigator (GREIN) software was used to obtain raw gene-level counts and filtered metadata for this dataset. Next generation knowledge discovery (NGKD) tools provided by BioJupies were used to obtain differentially regulated pathways, gene ontologies (GO), and gene signatures in the BM-HSCs. Finally, the L1000 Characteristic Direction Signature Search Engine (L1000CDS2) tool was used to identify specific drugs that reverse aging-associated gene signatures in old but healthy individuals. The down-regulation of signaling pathways such as longevity regulation, proteasome, Notch, apoptosis, nuclear factor kappa B (NFkB), and peroxisome proliferator-activated receptors (PPAR) signaling pathways in the BM-HSCs of healthy elderly. GO functions related to negative regulation of bone morphogenetic protein (BMP), telomeric DNA binding, nucleoside binding, calcium -dependent protein binding, chromatin-DNA binding, SMAD binding, and demethylase activity were significantly downregulated in the BM-HSCs of the elderly compared to the healthy young group. Importantly, potential drugs such as salermide, celestrol, cercosporin, dorsomorphin dihydrochloride, and LDN-193189 monohydrochloride that can reverse the aging-associated signatures in HSCs from healthy elderly were identified. The analysis of RNA-seq data based on NGKD techniques revealed a plethora of differentially regulated pathways, gene ontologies, and drugs with anti-aging potential to promote healthspan in the elderly.

Influence of donor age on liver transplantation outcomes: A multivariate analysis and comparative study.

The growing disparity between the rising demand for liver transplantation (LT) and the limited availability of donor organs has prompted a greater reliance on older liver grafts. Traditionally, utilizing livers from elderly donors has been associated with outcomes inferior to those achieved with grafts from younger donors. By accounting for additional risk factors, we hypothesize that the utilization of older liver grafts has a relatively minor impact on both patient survival and graft viability. To evaluate the impact of donor age on LT outcomes using multivariate analysis and comparing young and elderly donor groups. In the period from April 2013 to December 2018, 656 adult liver transplants were performed at the University Hospital Merkur. Several multivariate Cox proportional hazards models were developed to independently assess the significance of donor age. Donor age was treated as a continuous variable. The approach involved univariate and multivariate analysis, including variable selection and assessment of interactions and transformations. Additionally, to exemplify the similarity of using young and old donor liver grafts, the group of 87 recipients of elderly donor liver grafts (≥ 75 years) was compared to a group of 124 recipients of young liver grafts (≤ 45 years) from the dataset. Survival rates of the two groups were estimated using the Kaplan-Meier method and the log-rank test was used to test the differences between groups. Using multivariate Cox analysis, we found no statistical significance in the role of donor age within the constructed models. Even when retained during the entire model development, the donor age's impact on survival remained insignificant and transformations and interactions yielded no substantial effects on survival. Consistent insignificance and low coefficient values suggest that donor age does not impact patient survival in our dataset. Notably, there was no statistical evidence that the five developed models did not adhere to the proportional hazards assumption. When comparing donor age groups, transplantation using elderly grafts showed similar early graft function, similar graft (P = 0.92), and patient survival rates (P = 0.86), and no significant difference in the incidence of postoperative complications. Our center's experience indicates that donor age does not play a significant role in patient survival, with elderly livers performing comparably to younger grafts when accounting for other risk factors.

Inhibition of the histone methyltransferase EZH2 induces vascular stiffness.

Vascular stiffness increases with aging, obesity and hypertension and predicts cardiovascular risk. The levels of histone H3-lysine-27 methylation (H3K27me) and the histone methyltransferase EZH2 both decrease in aging vessels, driving vascular stiffness. The impact of EZH2 inhibitors on vascular stiffness is unknown. We tested the hypothesis that the EZH2 inhibitor GSK126, currently in development for cancer treatment, increases vascular stiffness and explored underlying molecular mechanisms. Young (3 month) and middle-aged (12 month) male mice were treated with GSK126 for 1-2 months and primary human aortic smooth muscle cells (HASMCs) from young male and female donors were treated with GSK126 for 24-48 h. Stiffness was measured in vivo by pulse wave velocity and in vitro by atomic force microscopy (AFM) and vascular structure was quantified histologically. Extracellular matrix proteins were studied by qRT-PCR, immunoblotting, zymography and chromatin immunoprecipitation. GSK126 treatment decreased H3K27 methylation (H3K27me) and increased acetylation (H3K27ac) in mouse vessels and in HASMCs. In GSK126-treated mice, aortic stiffness increased without changes in vascular fibrosis. EZH2 inhibition enhanced elastin fiber degradation and matrix metalloprotease-2 (MMP2) expression. In HASMCs, GSK126 treatment increased synthetic phenotype markers and intrinsic HASMCs stiffness by AFM with altered cytoskeletal structure and increased nuclear actin staining. GSK126 also increased MMP2 protein expression, activity and enrichment of H3K27ac at the MMP2 promoter in HASMCs. GSK126 causes vascular stiffening, inducing MMP2 activity, elastin degradation, and modulation of SMC phenotype and cytoskeletal stiffness. These findings suggest that EZH2 inhibitors used to treat cancer could negatively impact the vasculature by enhancing stiffness and merits examination in human trials.